Dicalcium phosphate dihydrate is used to a great extent as a carrier substance in the pharmaceutical industry, but the range of use thereof is limited to active substances which are not water-sensitive as under unfavourable conditions the dihydrate can already slowly separate off water from a temperature of 40° C. Therefore the use of dicalcium phosphate anhydride acquired increasing attraction as a carrier substance for drug forms, in particular for the direct tabletting of pharmaceutical products.
Dicalcium phosphate anhydride is generally produced by the neutralisation of phosphoric acid with a basic calcium compound, for example calcium hydroxide or calcium carbonate, at a temperature above 60° C. At lower temperatures dicalcium phosphate dihydrate or a mixture of dicalcium phosphate dihydrate and anhydride is produced. The dicalcium phosphate anhydride generally occurs in the form of fine crystals which are crushed in mills to form powder. The products obtained in that way are usually of an average grain size of smaller than 20 μm and are of a bulk density of between 500 and 900 g/l. Because of the high degree of fineness and the poor trickle flow capability which this involves, those anhydride products cannot be directly tabletted but have to be granulated prior to use in order to ensure an adequate flow capability which is required for uniformly filling the dies of the tabletting machines.
In order to avoid those disadvantages, a switch was made to using coarse-grain dicalcium phosphate anhydride for direct tabletting. By way of example U.S. Pat. No. 4,707,361 describes a coarse-grain dicalcium phosphate anhydride powder for tabletting with a grain size of at least 90% greater than about 44 μm and at least 95% smaller than about 420 μm and with a specific surface area of greater than 5 m2/g. That powder is produced by dehydrating dicalcium phosphate dihydrate.
DE-A-4 122 960 describes a process for producing coarse-grain dicalcium phosphate anhydride powder, in which at least 95% are of a grain size of over 45 μm and the mean grain diameter thereof is in the range of between 130 and 150 μm. That powder which is intended for direct tabletting is produced by a procedure whereby dilute phosphoric acid is provided at a temperature of between 70 and 90° C. and lime solution and further phosphoric acid are added, maintaining a pH-value of between 3 and 4.5. The pH-value is then adjusted to between 5.5 and 6.8 with lime solution.
Finally EP-A-0 644 156 describes, for drugs, cosmetics and foodstuffs, a dicalcium phosphate with a low water of hydration content and a specific surface area of between 20 and 60 m2/g, a bulk weight of a maximum of 200 g/l and a grain size of the primary particles of between 0.1 and 5 μm and a grain size of the agglomerates of between 2 and 10 μm. Manufacture is effected by precipitation from phosphoric acid and an alkaline calcium compound in the presence of an organic complexing compound and granulation by spray drying.
Now the object of the present invention is to obtain a dicalcium phosphate anhydride powder with superior trickle properties, by means of which, particularly in the direct tabletting of pharmaceutical preparations, increased amounts of calcium can be introduced into the preparation.